Schisandrin B, a dual positive allosteric modulator of GABAA and glycine receptors, alleviates seizures in multiple mouse models.

Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 µM, and application of SchB (10 µM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 µM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 µM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)ß2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.

TOM40 mediates the effect of TSPO on postpartum depression partially through regulating calcium homeostasis in microglia.

AIMS: To assess the effect of the translocator protein 18 kDa (TSPO) on postpartum depression and explore its mechanism. METHODS: Postpartum depression (PPD) mouse model was established, and flow cytometry, immunofluorescence, Western blot analysis, real-time quantitative PCR, adeno-associated virus (AAV), co-immunoprecipitation-mass spectrometry and immunofluorescence co-staining were used to detect the effect of TSPO ligand ZBD-2 on PPD mice. RESULTS: ZBD-2 inhibits the overactivation of microglia in the hippocampus and amygdala of PPD model mice. ZBD-2 not only inhibited the inflammation but also repressed the burst of reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Meanwhile, ZBD-2 protects mitochondria from LPS-induced damages through inhibiting the influx of calcium. ZBD-2 modulated the calcium influx by increasing the level of translocase of the outer mitochondrial membrane 40 (TOM40) and reducing the interaction of TSPO and TOM40. In addition, the effect of ZBD-2 was partially dependent on anti-oxidative process. Knockdown of TOM40 by adeno-associated virus (AAV) in the hippocampus or amygdala dramatically reduced the effect of ZBD-2 on PPD, indicating that TOM40 mediates the effect of ZBD-2 on PPD. CONCLUSIONS: TOM40 is required for the effect of ZBD-2 on treating anxiety and depression in PPD mice. This study reveals the role of microglia TSPO in PPD development and provides the new therapeutic strategy for PPD.

An Investigation of the Effects of B7-H4 Gene rs10754339 and miR-125a Gene rs12976445 on Cancer Susceptibility.

Objective: To investigate the effects of the B7-H4 gene rs10754339 and miR-125a gene rs12976445 on cancer susceptibility through a case-control study and meta-analysis. Methods: A total of 1,490 cancer patients (lung/gastric/liver/: 550/460/480) and 800 controls were recruited in this case-control study. The meta-analysis was performed by pooling the data from previous related studies and the present study. Results: The results of this study showed that in the Hubei Han Chinese population, the rs10754339 gene was significantly associated with the risk of lung and gastric cancer but not liver cancer, and the rs12976445 gene was significantly associated with the risk of lung cancer but not liver or gastric cancer. The meta-analysis results indicated that rs10754339 and rs12976445 contributed to cancer susceptibility in the Chinese population and also revealed a significant association between rs10754339 and breast cancer risk, as well as between rs12976445 and lung cancer risk. Conclusion: The B7-H4 gene rs10754339 and miR-125a gene rs12976445 may be the potential genetic markers for cancer susceptibility in the Chinese population, which should be validated in future studies with larger sample sizes in other ethnic populations.

[Transmission and Growth Characteristics of Severe PM2.5 Pollution Events from 2013 to 2021 in Xingtai, Hebei].

The correlation between the growth rate of PM2.5 with transport source, atmospheric circulation, and wind field were analyzed, focusing on the severe and above pollution process (SAAP) in Xingtai, Hebei Province from 2013 to 2021. The results showed that from 2013 to 2021, a total of 164 pollution processes and 103 SAAP occurred in Xingtai. In the ground circulation, although the probability occurrence of the inverted trough was low, the probability of pollution was the highest (61.1%), followed by the high-pressure control type (>50.0%). In the 500 hPa, the control of the straight westerly wind belt had the highest probability of severe and above pollution (20.7%), followed by the post-trough type (16.1%), with the highest occurrence frequency. In SAAP, the distribution of the PM2.5 hourly growth rate (ΔPM2.5) was mainly concentrated between ±150 µg·(m3·h)-1, and the PM2.5 hourly growth rate was positive (+ΔPM2.5), contributing 61.7%. Among them, the average proportion of explosive growth was 13.9% (from 2013 to 2021), and the overall trend was decreasing annually. In the full wind speed, in terms of occurrence frequency and pollution probability, north-east (NE) was the wind direction most closely related to air pollution, especially severe and above pollution. The mean value of ΔPM2.5 in SAAP was lower than that of quiet wind in most wind directions. However, in some of the east-north (EN) and south-west (SW) wind direction intervals, the mean ΔPM2.5 in moderate wind speed was significantly higher than that of quiet wind (related to pollution transmission). The impact of larger wind speed on ΔPM2.5 was more complicated. The backward trajectories showed that the backward trajectories of slow, rapid, and explosive growth in SAAP could be divided into three main paths:west-north, east-north, and south. With the acceleration of the growth rate, the proportion of the west-north air mass gradually increased. The humidity (RH) of the slow-growth air mass was relatively large (more than 80% RH>50%), the relative humidity of the rapidly growing air mass was relatively concentrated (mainly distributed in 35%-55%), and the proportion of low-humidity (<50%) air masses increased significantly (by approximately 63%) in the explosive growth. The simulation analysis showed that the types of SAAP pollution could be divided into five categories:local accumulation, east-northern transmission, north-west transmission, mixed transmission, and south transmission. Among them, the proportion of mixed transmission was the highest, followed by that of the north-west transmission. The high and low-altitude configurations with the highest occurrence probability among the southerly transmission, the local accumulation type, and the north-easterly transport type were all high-altitude trough rear type combined with ground equalization field type. Among the north-westerly type, the high-pressure on the ground with the behind trough on high-altitude had the highest probability of occurrence. In mixed transmission, the probabilities of various circulation ratios were relatively balanced.

[Distributions of Antibiotic Resistance Genes and Microbial Communities in the Nearshore Area of the Yangtze River Estuary].

Due to the extensive use of antibiotics, the resistance of microorganisms to antibiotics in the environment is increasing, and the problem of antibiotic resistance genes (ARGs) is becoming more and more severe, which seriously threatens ecological security and human health. In order to study the distribution characteristics of ARGs and the microbial community in different media in the coastal area of the Yangtze River Estuary, water and sediment samples from eight sites were collected through a field investigation. Two sulfonamide resistance genes ([STBX]sul1, sul2[STBZ]) and six tetracycline resistance genes (tetM, tetC, tetX, tetA, tetO, and tetQ), one integrase gene intI[STBX]1[STBZ], 16S rRNA gene, and the microbial community were detected and analyzed. The results showed that the detection rate of 10 resistance genes in the coastal area of the Yangtze River Estuary was 100%. [STBX]intI1[STBZ] was significantly positively correlated with various ARGs in the water samples. Proteobacteria and Bacteroidota were the dominant bacteria phyla in the water environment of the Yangtze River Estuary. Chloroplast was the main bacteria genus in water, and Chloroplast and Nitrospira were the main bacteria genera in sediment. In water, Nitrospirota was the common potential host of four tetracycline resistance genes (tetX, tetA, tetO, and tetQ). In sediments, Sva0485 was a potential host community shared by [STBX]sul1 and intI1[STBZ]. The distribution of the microbial community was an important factor affecting the migration and transformation of ARGs in the nearshore area of the Yangtze River Estuary.

Effect of moxibustion on immune function homeostasis in rats with diarrhea irritable bowel syndrome based on SCF/c-kit signaling pathway / 中国针灸

OBJECTIVE@#To observe the effects of moxibustion on the stem cell factor (SCF)/tyrosine kinase receptor (c-kit) signaling pathway and immune function in rats with diarrhea irritable bowel syndrome (IBS-D), and to explore the mechanism of moxibustion for IBS-D.@*METHODS@#Among 52 young rats born from 6 healthy pregnant SPF rats, 12 rats were randomly selected into the normal group, and the remaining 40 rats were treated with the three-factor combination method of maternal separation, acetic acid enema and chronic restraint stress to establish the IBS-D rat model. Thirty-six rats with successful IBS-D model were randomly divided into a model group, a moxibustion group, and a medication group, 12 rats in each group. The rats in the moxibustion group were treated with suspension moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37); the rats in the medication group were treated with intragastric administration of rifaximin suspension (150 mg/kg). All the treatments were given once a day for 7 consecutive days. The body mass, loose stool rate (LSR), the minimum volume threshold when abdominal withdrawal reflex (AWR) scored 3 were measured before acetic acid enema (35 days old), after modeling (45 days old), and after intervention (53 days old). After intervention (53 days old), HE staining was used to observe the morphology of colon tissue, and spleen and thymus coefficients were measured; ELISA method was used to detect serum inflammatory factors (tumor necrosis factor a [TNF-a], interleukin [IL]-10, IL-8), T-lymphocyte subsets (CD+4, CD+8, CD+45), value of CD+4/CD+8 and immune globulin (IgA, IgG, IgM); real-time PCR method and Western blot method was used to detect the expression of SCF, c-kit mRNA and protein in colon tissue; immunofluorescence staining method were used to detect positive expression of SCF and c-kit.@*RESULTS@#After intervention, compared with the normal group, in the model group, the body mass and the minimum volume threshold when AWR scored 3 were decreased (P<0.01), LSR, spleen and thymus coefficients, serum levels of TNF-α, IL-8, CD+4, CD+45, CD+4/CD+8, IgA, IgG, IgM were increased (P<0.01), serum IL-10 level and protein and mRNA expression of SCF and c-kit in colon tissue were decreased (P<0.01), and the positive expression of SCF and c-kit was decreased (P<0.01). Compared with the model group, in the moxibustion group and the medication group, the body mass and the minimum volume threshold when AWR scored 3 were increased (P<0.01, P<0.05), LSR, spleen and thymus coefficients, serum levels of TNF-α, IL-8, CD+4, CD+8, CD+45, CD+4/CD+8, IgA, IgG, IgM were decreased (P<0.01, P<0.05), serum IL-10 level and protein and mRNA expression of SCF and c-kit in colon tissue were increased (P<0.01), and the positive expression of SCF and c-kit was increased (P<0.01). Compared with the medication group, in the moxibustion group, the level of serum CD+4 was decreased (P<0.05), the value of CD+4/CD+8 was increased (P<0.01), and there was no significant difference in other indexes (P>0.05). The expression of SCF and c-kit mRNA was positively correlated with the minimum volume threshold when AWR scored 3 and IL-10 (P<0.01), and negatively correlated with remaining indexes (P<0.01, P<0.05).@*CONCLUSION@#Moxibustion could reduce visceral hypersensitivity, improve symptoms of abdominal pain and diarrhea in IBS-D rats, and its mechanism may be related to up-regulation of the expression of SCF/c-kit signaling pathway and improvement of IBS-D immune function.

Anti-inflammation effect of moxibustion for rats with diarrhea-predominant irritable bowel syndrome based on multiple miRNAs regulating NF-κB signal pathway / 中国针灸

OBJECTIVE@#To observe the effect of moxibustion on the regulation of nuclear factor-kappa B (NF-κB) and inflammatory factors by multiple microRNAs (miRNAs) in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and to explore the anti-inflammatory mechanism of moxibustion on IBS-D.@*METHODS@#Twelve of 52 newborn rats were randomly selected into a normal group. The remaining rats were made into IBS-D model. A total of 36 rats with successful model were randomly divided into a model group, a medication group and a moxibustion group, 12 rats in each group. The rats in the medication group were intraperitoneally injected with pyrrolidine dithiocarbamate (PDTC). The rats in the moxibustion group were treated with moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for 20 min each time. All the intervention was given once a day for 7 days. Before and after modeling as well as after intervention, the body mass, loose stool rate and the minimum volume threshold of abdominal withdrawal reflex (AWR) were measured. After intervention, the contents of serum tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-8 were detected by ELISA method; the morphology of colon tissues was observed by HE staining, and the expressions of miR-155, miR-125b, miR-29b, miR-31, miR-18a and NF-κB p65 mRNA in colon tissues were detected by real-time PCR. The expressions of NF-κB p65, TNF-α, IL-1β and IL-8 protein in colon tissues were detected by immunofluorescence.@*RESULTS@#After modeling, the body mass and the minimum volume threshold of AWR in the model group were lower than those in the normal group (P<0.01); the rates of loose stool in the model group were higher than those in the normal group (P<0.01); after intervention, in the model group, the inflammatory infiltration of colon tissues was obvious, and the serum levels of TNF-α, IL-1 β, IL-8 were higher than those in the normal group (P<0.05); the expression of miR-155, miR-125b, miR-29b, miR-31, miR-18a and NF-κB p65 mRNA in colon tissues was higher than that in the normal group (P<0.05); the protein expression of NF-κB p65, TNF-α, IL-1β, IL-8 was also higher than that in the normal group (P<0.01). After intervention, the body mass and the minimum volume threshold of AWR in the medication group and the moxibustion group were both higher than those in the model group (P<0.05); the loose stool rate in the medication group and the moxibustion group were lower than those in model group (P<0.05); the inflammatory cells infiltration in the colon tissues was less, the serum levels of TNF-α, IL-1β and IL-8 as well as the protein expression of NF-κB p65, TNF-α, IL-1β and IL-8 in the colon tissues in the medication group and the moxibustion group were lower than those in the model group (P<0.05, P<0.01). The expression of miR-125b, miR-31, miR-18a and NF-κB p65 mRNA in the medication group were lower than those in the model group (P<0.05). The expression of miR-155, miR-125b, miR-29b, miR-31, miR-18a and NF-κB p65 mRNA in the moxibustion group were lower than those in the model group (P<0.05). The miR-155, miR-125b, miR-29b, miR-31, miR-18a were positively correlated with NF-κB p65 mRNA (0<r<1, P<0.01).@*CONCLUSION@#The anti-inflammatory mechanism of moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for IBS-D rats may be related to regulating multiple miRNAs to inhibit NF-κB signal pathway and reduce the expression of inflammatory factors.

Comparative Pharmacokinetics of Gallic Acid After Oral Administration of Gallic Acid Monohydrate in Normal and Isoproterenol-Induced Myocardial Infarcted Rats.

Gallic acid (GA) is a polyphenolic natural product widely distributed in food, beverage, and traditional Chinese herbs with beneficial effects on the cardiovascular system. In this research, a comparative study was conducted to investigate the possible difference of pharmacokinetic process in normal and isoproterenol-induced myocardial infarcted rats after oral administration of GA monohydrate with the dose of 50 and 100 mg/kg, respectively. Quantification of GA in rat plasma was achieved by using a simple and rapid high-performance liquid chromatographic method. The results revealed that pharmacokinetics of GA were greatly different between normal and pathological state. GA exhibited slower absorption into the bloodstream, and yielded 1.7-fold (50 mg/kg GA) and 1.3-fold (100 mg/kg GA) less values of area under concentration-time curve as well as 2.5-fold lower of maximum blood concentration (Cmax) in MI rats than those in normal rats. In addition, significant prolonged T1/2 and MRT as well as decreased CL were also registered in MI rats. Our findings suggest that myocardial infarction could alter the pharmacokinetic process of GA, and thus the potential pharmacokinetic differences of herbal preparations (or dietary nutrition) containing GA between normal and pathological conditions should be brought to the forefront seriously in clinical practice.

Risk Factors Study for Stroke in Patients with Type 2 Diabetes Based on CHIRA Database / 中国药学杂志

OBJECTIVE: To analyze the risk factors for stroke in patients with type 2 diabetes in China by using CHIRA database and control the expenditure of medicine for stroke patients and reducing the economic burden of medical insurance funds. METHODS: The data of T2DM patients in the 2015 CHIRA database were collected. The new stroke patients were used as a baseline group. The stroke-free patients who have the similar baseline were selected as the control group by using the PSM. At last, Logistic regression model was used to analyze the relationship between chronic complications of type 2 diabetes and stroke in T2DM patients. RESULTS: Four thousand four hundred and fifty patients were included after using the PSM. Two thousand one hunderd and forty-five(48.20%) patients were diagnosed with chronic complications and 1 138 patients were diagnosed with stroke (53.05%), higher than patietnts who have no chronic complications (47.16%, P<0.0001). Logistic regression model showed that cardiovascular complication(OR=1.19,95%CI:1.05-1.34) and peripheral neuropathy (OR=1.34,95%CI:1.11-1.62) are independent risk factors for stroke. CONCLUSION: Cardiovascular complication and peripheral neuropathy of patients with type 2 diabetes are independent risk factors for stroke.